PURPOSE: The prostaglandin F2alpha (PGF2α) analogue bimatoprost lowers intraocular pressure (IOP) by increasing uveoscleral outflow at doses shown to elicit redness of the eye. With the aim to enhance the IOP-lowering effect of bimatoprost we studied NCX 470 [(S,E)-1-((1R,2R,3S,5R)-2-((Z)-7-(ethylamino)-7-oxohept-2-enyl)-3,5-dihydroxycyclopentyl)-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate], a dual-acting compound combining bimatoprost with nitric oxide (NO) known to mainly act via relaxation of trabecular meshwork and Schlemm's canal. METHODS: New Zealand white rabbits with transient hypertonic saline-induced IOP elevation (tOHT-rabbits), cynomolgus monkeys with laser-induced ocular hypertension (OHT-monkeys), and normotensive dogs (ONT-dogs) were used. The levels of NCX 470, bimatoprost, and bimatoprost acid were determined in aqueous humor (AH), cornea (CR), and iris/ciliary body (ICB) by liquid chromatography-mass spectrometry/mass (LC-MS/MS), while cGMP in AH and ICB was monitored using an enzyme immunoassay (EIA) kit in pigmented Dutch Belted rabbits. RESULTS: NCX 470 (0.14%, 30 μL) lowered IOP in tOHT-rabbits with an E(max) of -7.2 ± 2.8 mm Hg at 90 minutes. Bimatoprost at equimolar dose (0.1%, 30 μL) was noneffective in this model. NCX 470 (0.042%, 30 μL) was more effective than equimolar (0.03%, 30 μL) bimatoprost in ONT-dogs (IOP change, -5.4 ± 0.7 and -3.4 ± 0.7 mm Hg, respectively, P < 0.05) and in OHT-monkeys (IOP change, -7.7 ± 1.4 and -4.8 ± 1.7 mm Hg, respectively, P < 0.05) at 18 hours post dosing. NCX 470 (0.042%, 30 μL) or bimatoprost (0.03%, 30 μL) resulted in similar bimatoprost acid exposure in AH, CR, and ICB while cGMP was significantly increased in AH and ICB at 18 and 24 hours after NCX 470 dosing. CONCLUSIONS: NCX 470 lowers IOP more than equimolar bimatoprost in three animal models of glaucoma by activating PGF2α and NO/cGMP signaling pathways.
PURPOSE: The prostaglandin F2alpha (PGF2α) analogue bimatoprost lowers intraocular pressure (IOP) by increasing uveoscleral outflow at doses shown to elicit redness of the eye. With the aim to enhance the IOP-lowering effect of bimatoprost we studied NCX 470 [(S,E)-1-((1R,2R,3S,5R)-2-((Z)-7-(ethylamino)-7-oxohept-2-enyl)-3,5-dihydroxycyclopentyl)-5-phenylpent-1-en-3-yl 6-(nitrooxy)hexanoate], a dual-acting compound combining bimatoprost with nitric oxide (NO) known to mainly act via relaxation of trabecular meshwork and Schlemm's canal. METHODS: New Zealand white rabbits with transient hypertonicsaline-induced IOP elevation (tOHT-rabbits), cynomolgus monkeys with laser-induced ocular hypertension (OHT-monkeys), and normotensive dogs (ONT-dogs) were used. The levels of NCX 470, bimatoprost, and bimatoprost acid were determined in aqueous humor (AH), cornea (CR), and iris/ciliary body (ICB) by liquid chromatography-mass spectrometry/mass (LC-MS/MS), while cGMP in AH and ICB was monitored using an enzyme immunoassay (EIA) kit in pigmented Dutch Belted rabbits. RESULTS:NCX 470 (0.14%, 30 μL) lowered IOP in tOHT-rabbits with an E(max) of -7.2 ± 2.8 mm Hg at 90 minutes. Bimatoprost at equimolar dose (0.1%, 30 μL) was noneffective in this model. NCX 470 (0.042%, 30 μL) was more effective than equimolar (0.03%, 30 μL) bimatoprost in ONT-dogs (IOP change, -5.4 ± 0.7 and -3.4 ± 0.7 mm Hg, respectively, P < 0.05) and in OHT-monkeys (IOP change, -7.7 ± 1.4 and -4.8 ± 1.7 mm Hg, respectively, P < 0.05) at 18 hours post dosing. NCX 470 (0.042%, 30 μL) or bimatoprost (0.03%, 30 μL) resulted in similar bimatoprost acid exposure in AH, CR, and ICB while cGMP was significantly increased in AH and ICB at 18 and 24 hours after NCX 470 dosing. CONCLUSIONS:NCX 470 lowers IOP more than equimolar bimatoprost in three animal models of glaucoma by activating PGF2α and NO/cGMP signaling pathways.
Authors: Francesco Impagnatiello; Elena Bastia; Nicoletta Almirante; Stefania Brambilla; Brigitte Duquesroix; Angela C Kothe; Michael V W Bergamini Journal: Br J Pharmacol Date: 2018-05-24 Impact factor: 8.739
Authors: Marco Blangetti; Barbara Rolando; Elisabetta Marini; Konstantin Chegaev; Stefano Guglielmo; Loretta Lazzarato; Laura Lucarini; Emanuela Masini; Roberta Fruttero Journal: ACS Med Chem Lett Date: 2017-09-13 Impact factor: 4.345
Authors: Ester Reina-Torres; Michael L De Ieso; Louis R Pasquale; Michael Madekurozwa; Joseph van Batenburg-Sherwood; Darryl R Overby; W Daniel Stamer Journal: Prog Retin Eye Res Date: 2020-11-28 Impact factor: 21.198
Authors: Thomas R Walters; Angela C Kothe; José L Boyer; Dale W Usner; Krisol Lopez; Brigitte Duquesroix; Robert D Fechtner; Tomas Navratil Journal: J Glaucoma Date: 2022-04-06 Impact factor: 2.290
Authors: Elena Bastia; Carol B Toris; Stefania Brambilla; Corinna Galli; Nicoletta Almirante; Michael V W Bergamini; Emanuela Masini; Silvia Sgambellone; Andrea M Unser; Feryan Ahmed; Karen Y Torrejon; Tomas Navratil; Francesco Impagnatiello Journal: Invest Ophthalmol Vis Sci Date: 2021-03-01 Impact factor: 4.799
Authors: Stefan Muenster; Wolfgang S Lieb; Gregor Fabry; Kaitlin N Allen; Shivani S Kamat; Ann H Guy; Ana C Dordea; Leandro Teixeira; Robert E Tainsh; Binglan Yu; Wei Zhu; Nicole E Ashpole; Rajeev Malhotra; Peter Brouckaert; Donald B Bloch; Marielle Scherrer-Crosbie; W Daniel Stamer; Markus H Kuehn; Louis R Pasquale; Emmanuel S Buys Journal: Invest Ophthalmol Vis Sci Date: 2017-09-01 Impact factor: 4.799